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ß-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee

From the Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne; United Kingdom Children's Cancer Study Group, University of Leicester, Leicester; Department of Radiotherapy, Cookridge Hospital, Leeds, United Kingdom

Address reprint requests to D.W. Ellison, MD, PhD, Northern Institute for Cancer Research, Paul O'Gorman Building, University of Newcastle, Newcastle-upon-Tyne, NE2 4HH, United Kingdom; e-mail: D.W.Ellison{at}ncl.ac.uk

	ABSTRACT

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PURPOSE: Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the ß-catenin protein is associated with activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas. We tested the hypothesis that nuclear immunoreactivity for ß-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear ß-catenin immunoreactivity and mutations of CTNNB1 and APC.

PATIENTS AND METHODS: Medulloblastomas from children entered onto the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial (n = 109) were examined for ß-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathologic variables, principally outcome.

RESULTS: Children with medulloblastomas that showed a nucleopositive ß-catenin immunophenotype (27 of 109; 25%) had significantly better overall (OS) and event-free (EFS) survivals than children with tumors that showed either membranous/cytoplasmic ß-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For ß-catenin nucleopositive and nucleonegative medulloblastomas, 5-year OS was 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%), and 5-year EFS was 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Mutations in CTNNB1 were found exclusively among medulloblastomas that demonstrated nuclear ß-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with ß-catenin nucleopositive large cell/anaplastic medulloblastomas and ß-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis.

CONCLUSION: Nuclear accumulation of ß-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.

	INTRODUCTION

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Advances in treatment regimens for medulloblastoma, an embryonal neuroepithelial tumor of the cerebellum and the most common malignant CNS tumor in children, have improved 5-year survival rates for standard-risk patients to approximately 70%. However, many surviving children have long-term cognitive and/or neuroendocrine adverse effects, and survival rates for high-risk patients are as low as 25%.^1,2 Currently, the two principal scientific challenges presented by medulloblastomas are: (1) identifying pathobiologic correlates of its heterogeneous behavior to facilitate therapeutic stratification and reduce adverse treatment effects, and (2) finding novel therapies for those children with biologically aggressive tumors.³

One approach to disease stratification is to combine histopathologic evaluation with an assessment of molecular abnormalities associated with biologic behavior or therapeutic response.⁴ The occurrence of medulloblastoma in type 2 Turcot's syndrome, in which patients have multiple colonic polyps and germline mutations in the APC tumor suppressor gene, has suggested that abnormalities of the Wnt/Wingless (Wnt/Wg) pathway could be involved in the development of sporadic medulloblastomas.^5,6 Subsequently, mutations in components of the Wnt/Wg pathway, including APC and CTNNB1 (encoding ß-catenin), have been consistently demonstrated in approximately 15% of sporadic medulloblastomas and are predicted to cause aberrant pathway activation.^7-10

The critical downstream effector of the canonical Wnt/Wg pathway is ß-catenin.⁶ Cytoplasmic ß-catenin is regulated by a multimeric protein complex, which contains the APC, GSK-3ß, and AXIN proteins. In the "pathway-inactive" state, GSK-3ß phosphorylates ß-catenin, signaling it for degradation through the ubiquitin-proteasome system. Pathway activation destabilizes the protein complex, upregulating levels of ß-catenin and enhancing its translocation to the nucleus. Here, it acts as a coactivator of Tcf/Lef transcription factors, which regulate genes involved in cell cycle progression, apoptosis, and differentiation. Thus, nuclear accumulation of ß-catenin is a marker for physiologic or abnormal Wnt/Wg pathway activation.

The purpose of this study of medulloblastomas was twofold: (1) to test the hypothesis that nuclear accumulation of ß-catenin is a prognostic marker, and (2) to evaluate any association between ß-catenin status and the presence of APC and CTNNB1 mutations.

	PATIENTS AND METHODS

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Clinicopathologic Details
Medulloblastomas (n = 109) from children registered on the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial protocol were provided by several SIOP/UKCCSG centers.^11-13 Cohort size was determined by tissue availability. Of this study's cohort, 71 children had been part of the randomized trial described previously,¹¹ the remainder having been treated according to protocol. Tumors were classified histopathologically as classic (n = 89; 82%) or large cell/anaplastic (n = 20; 18%) variants.^14,15 Poor recruitment of desmoplastic tumors (n = 5) precluded the inclusion of this variant in the study. Clinical data, including current status, were available from the UKCCSG data center. Median age at diagnosis was 8.3 years (range, 3.0 to 16.8 years), and there was a prevalence of males (1.6:1). Overall, a greater proportion of patients (60%) had received radiotherapy/chemotherapy than radiotherapy alone.¹¹ Median survival was 7.5 years. Metastatic disease at presentation was demonstrated by central radiologic review of 14 patients (all Chang stage M3), all of which were part of a previously described series of 68 patients with M2-3 disease.¹³

Immunohistochemistry
Immunohistochemistry was undertaken on 5-µm sections of formalin-fixed paraffin wax-embedded (FFPE) tumors, using a microwave antigen retrieval step carried out in 0.01M citrate buffer (pH 6.0) for 10 minutes. A primary antibody to ß-catenin (BD Transduction Laboratories, San Jose, CA) was applied at a concentration of 1:100. Antigen-antibody complexes were revealed using a biotinylated antimouse IgG second stage and a Vectastain ABC Elite Kit (Vector Laboratories, Burlingame, CA) with diaminobenzidine as the chromogen. A section containing a colonic carcinoma and adjacent normal colonic epithelium was used as a control.

Mutational Analysis of CTNNB1 and APC by Direct DNA Sequencing
Genomic DNA was extracted from FFPE tumors using a DNeasy tissue kit (Qiagen, Crawley, UK), according to manufacturer's instructions. Polymerase chain reaction (PCR) products spanning (1) the GSK-3ß phosphorylation domain of ß-catenin (nucleotides 791-1070, Genbank accession number X89579; Invitrogen, Paisley, UK), and (2) the mutation cluster region of APC (nucleotides 3784-4627, Genbank accession number NM000038; Invitrogen, Paisley, UK) were generated using specific PCR primers and standard PCR conditions (Invitrogen, Paisley, UK; available at http://www.ncl.ac.uk/nicr/research/ebtd/paed/Ellison_et_al_primers.pdf). PCR products were sequenced on forward and reverse strands using a CEQ DTCS kit, and analyzed on a CEQ 2000XL DNA analysis system (both Beckman Coulter, Fullerton, CA). All mutations detected were confirmed by independent replicate analysis.

Statistical Methods
Survival curves were produced and log-rank tests performed to compare overall survival (OS) and event-free survival (EFS) in accordance with various potential prognostic indicators. OS was defined as the time between date of diagnosis and date of death. EFS was defined as the time between date of diagnosis and date of first event, which was recurrence or death from any cause. Patients still alive at the end of the study were censored at the date of last follow-up. CIs for OS and EFS were calculated using Greenwood's formula. All observed prognostic variables were tested individually in a Cox proportional hazards model using the change in log likelihood from the null model.¹⁶ Those shown to be significant (P < .05) were entered into a multivariate model in a stepwise procedure taking a P value of .05 to enter and .05 to be removed.¹⁷ The final analysis was performed in January 2005.

	RESULTS

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ß-Catenin Immunohistochemistry
There were two principal patterns of ß-catenin immunoreactivity in medulloblastoma cells; cytoplasmic staining and combined cytoplasmic/nuclear staining (Fig 1). ß-catenin immunoreactivity of the cytoplasmic membrane alone characterized a proportion of cells in some tumors. A few medulloblastomas were devoid of ß-catenin immunoreactivity, but most showed at least focal labeling. Combined cytoplasmic/nuclear ß-catenin staining tended to characterize sheets or groups of cells, rather than scattered single cells, and could be categorized as strong/widespread or moderate/patchy. Overall, nuclear ß-catenin immunoreactivity, indicative of Wnt/Wg pathway activation, was detected in 27 (25%) of 109 medulloblastomas, being strong in 11 of 27 and moderate in 16 of 27 of the tumors.

View larger version (40K): [in this window] [in a new window]   Fig 1. Immunohistochemistry with an antibody to ß-catenin reveals (A) strong combined cytoplasmic and nuclear reactivity and (B) staining in the cytoplasm, but not nuclei, of these classic medulloblastomas. Electropherogram (C) illustrating a ß-catenin mutation (codon 32 GAC>AAC; ASP>ASN; X87838–see arrow) detected in a classic medulloblastoma by direct DNA sequencing.

Clinicopathologic Correlates of ß-Catenin Status
There was a significant association between ß-catenin immunoreactivity and outcome, both in terms of OS (P = .0015; Fig 2A) and EFS (P = .0026; Fig 2B). Patients with ß-catenin nucleopositive medulloblastomas had much better OS and EFS compared with those with nucleonegative tumors; 5-year OS 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%) respectively, and 5-year EFS 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Only three of 27 children who developed a medulloblastoma with a nuclear ß-catenin immunophenotype have relapsed. One of these three children is alive, 9 years postdiagnosis, and two have died, with overall survival times of 4.8 years and 5.1 years. Neither of these two children had metastatic disease at presentation, and the tumors from both were classic variants showing moderate nuclear ß-catenin immunoreactivity. CTNNB1 was wild type in one, but there was a CTNNB1 mutation (ASP32TYR) in the other. The remaining 24 children are alive without disease, having a median follow-up period of 7.6 years (range, 4.2 to 11.1 years). There was no significant association between ß-catenin status and either age or sex.

View larger version (5K): [in this window] [in a new window]   Fig 2. Kaplan-Meier overall (A) and event-free (B) survival curves for children with ß-catenin nucleopositive/nucleonegative medulloblastomas (P = .0015 for OS, P = .0026 for EFS; logrank tests).

Central radiologic review revealed metastatic disease at presentation in 14 of 109 children. Moderate ß-catenin nucleopositivity was present in tumors from three of these 14 children, all of whom are still alive 7.5 to 10.8 years postdiagnosis. In contrast, of the 11 of 14 children with ß-catenin nucleonegative medulloblastomas and metastatic disease at presentation, only three are still alive.

Repeating the survival analyses after excluding patients with metastatic disease from the cohort made no difference to the significance of any results. Those children with ß-catenin nucleopositive medulloblastomas (n = 24) had a significantly better outcome than those children (n = 71) with ß-catenin nucleonegative tumors (5-year OS, 91.3%; 95% CI, 79.7% to 100% v 68.3%; 95% CI, 57.2% to 79.3%, respectively; P = .009; 5-year EFS, 87.5%; 95% CI, 74.2% to 100% v 63%; 95% CI, 51.7% to 74.3%, respectively; P = .016), and patients with classic medulloblastomas (n = 76) had a significantly better outcome than those patients (n = 19) with LC/A tumors (5-year OS, 79.4%; 95% CI, 70% to 88.7% v 52.6%; 95% CI, 30.2% to 75.1%, respectively; P = .018; 5-year EFS, 74.7%; 95% CI, 64.9% to 84.6% v 47.4%; 95% CI, 24.9% to 69.8%, respectively; P = .014).

Several clinicopathologic variables, including those found previously to be of prognostic significance in SIOP/UKCCSG PNET3 trial patients, were entered into Cox proportional hazards models for OS and EFS (Tables 1 and 2, respectively). ß-catenin nuclear immunoreactivity and pathologic variant were independent prognostic indicators for both OS and EFS, whereas time to complete radiotherapy was an independent prognostic indicator for EFS. Metastatic disease was excluded as a variable from these analyses because there were too few patients (n = 14). However, when the analyses were repeated for the cohort minus patients with metastatic disease (n = 95), alterations to hazard ratios and P values were minimal and insignificant (data not shown).

	DISCUSSION

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Our study was undertaken on tumors from a subset of children enrolled onto the SIOP/UKCCSG PNET3 trial.^11-13 Clinical and pathologic indices for this subset closely match those of the original trial cohort.^11,12,15 In addition, the results of our univariate and multivariate survival analyses mirror those for the original trial cohort, with only one exception; EFS was significantly different for each treatment arm in the original trial cohort, but not in the current study.^11,12 There was a trend toward improved EFS with preradiotherapy chemotherapy if patients with metastatic disease were excluded from our study's cohort (5-year EFS, 74.7%; 95% CI, 62.7% to 86.6%, for preradiotherapy chemotherapy v 64.3%; 95% CI, 49.8% to 78.8%, respectively; P = .31). However, we have shown that the principal findings of this study are unaltered by the inclusion or exclusion, in the analyzed cohort, of patients that present with metastatic disease.

Because ß-catenin immunoreactivity can be assessed alongside tumor histopathology in FFPE tissue, its utility as a potential prognostic marker in medulloblastoma is greater than those markers that can be assayed only in freshly frozen tissue. However, its integration into refined classification schemes incorporating histopathologic and molecular evaluation will depend on whether it is an independent marker of biologic behavior or therapeutic response. Our data suggest that this is the case. We also noted that children with ß-catenin nucleopositive tumors in combination with metastatic disease at presentation or LC/A histopathology did not have the expected poor outcome. There were three children with metastatic disease and a ß-catenin nucleopositive tumor. All three children have survived 7.5 to 10.8 years postdiagnosis. Furthermore, all the children with ß-catenin nucleopositive LC/A medulloblastomas have survived 5 to 10.7 years postdiagnosis.

We have previously analyzed about half of the current series of tumors for loss of chromosome 17p and MYCC/MYCN amplification, which are cytogenetic markers of a poor prognosis in medulloblastoma.²⁷ Of the tumors in this cohort showing ß-catenin nucleopositivity, none showed loss of 17p or MYCN amplification, and only one demonstrated MYCC amplification. This medulloblastoma combined MYCC amplification in 20% of its cells with moderate/patchy nuclear ß-catenin immunoreactivity, and was notable for affecting one of only two children who died as a result of a ß-catenin–nucleopositive tumor. The full molecular data set for these 60 medulloblastomas is available online (http://www.ncl.ac.uk/nicr/research/ebtd/paed/Ellison_et_al.htm). Overall, our data indicate that ß-catenin immunoreactivity is likely to be a valuable marker in histopathologic/molecular classifications of medulloblastoma; ß-catenin nucleopositive medulloblastomas are uncommonly associated with clinicopathologic or molecular markers of an adverse prognosis, and when they are, prolonged survival is possible. Among proposed molecular markers of outcome in medulloblastoma, only ß-catenin nuclear immunoreactivity and TrkC overexpression have been associated with a good outcome,^4,28 offering the potential for stratifying patients into therapeutic regimens that produce less long-term cognitive adverse effects.

Our results indicate that missense point mutations affecting the GSK-3ß phosphorylation domain of CTNNB1 are associated with aberrant nuclear accumulation of ß-catenin in about two thirds of medulloblastomas. All detected mutations alter critical residues, in which mutations have been described in other cancers, and would be predicted to impair ß-catenin phosphorylation and degradation, leading to its nuclear accumulation.⁶ APC mutations were not associated with ß-catenin nuclear accumulation in our series. Only missense point mutations of APC have been observed in medulloblastoma,^9,10 in contrast with the inactivating deletions and truncating mutations that are commonly observed in other cancers and result in Wnt/Wg pathway activation.²⁹ Together, these results suggest that the APC mutations observed in medulloblastoma do not play a significant role in Wnt/Wg pathway activation, but may exert any functional effects through alternative mechanisms.

Although we cannot exclude the involvement of mutations outside the GSK-3ß phosphorylation domain of CTNNB1 or the mutation cluster region of APC, Wnt/Wg pathway activation in medulloblastoma appears to result from alternative mechanisms to CTNNB1 or APC mutation in a significant proportion (40%) of cases. Alternative tumor-specific mechanisms of pathway activation have been reported, including upregulation of the Akt oncogene, overexpression of Pin1, and mutation or inactivation of the AXIN1, SIAH1, and SFRP family of candidate tumor suppressor genes.^30-34 The potential role of these in pathway activation now requires investigation in medulloblastoma.

In conclusion, ß-catenin nuclear immunoreactivity appears to be a marker of good prognosis in medulloblastoma. Its utility should now be tested alongside other clinicopathologic and molecular prognostic indicators, such as histopathologic variant, loss of chromosome 17p, MYC amplification, and TrkC overexpression, in biologic studies attached to the SIOP/UKCCSG PNET4 trial and similar trials elsewhere.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
Thanks are due to Andrew Brown and Janet Thompson, of the Department of Neuropathology, Newcastle General Hospital, for technical assistance, and to Kath Robinson at the UKCCSG data center. The collaboration of staff in all centers across Europe that contributed to the SIOP PNET3 trial is gratefully acknowledged.

	NOTES

 
Supported by Grants from the Samantha Dickson Research Trust and the Faculty of Medical Sciences, University of Newcastle. The United Kingdom Children's Cancer Study Group is supported by Cancer Research UK.

This research was approved by the Newcastle and North Tyneside Local Research Ethics Committee and by the Biological Studies Committee of the United Kingdom Children's Cancer Study Group.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted February 21, 2005; accepted July 22, 2005.

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